Association of mineral and bone biomarkers with adverse cardiovascular outcomes and mortality in the German Chronic Kidney Disease (GCKD) cohort

Mineral and bone disorder (MBD) in chronic kidney disease (CKD) is tightly linked to cardiovascular disease (CVD). In this study, we aimed to compare the prognostic value of nine MBD biomarkers to determine those associated best with adverse cardiovascular (CV) outcomes and mortality. In 5 217 participants of the German CKD (GCKD) study enrolled with an estimated glomerular filtration rate (eGFR) between 30–60 mL·min−1 per 1.73 m2 or overt proteinuria, serum osteoprotegerin (OPG), C-terminal fibroblast growth factor-23 (FGF23), intact parathyroid hormone (iPTH), bone alkaline phosphatase (BAP), cross-linked C-telopeptide of type 1 collagen (CTX1), procollagen 1 intact N-terminal propeptide (P1NP), phosphate, calcium, and 25-OH vitamin D were measured at baseline. Participants with missing values among these parameters (n = 971) were excluded, leaving a total of 4 246 participants for analysis. During a median follow-up of 6.5 years, 387 non-CV deaths, 173 CV deaths, 645 nonfatal major adverse CV events (MACEs) and 368 hospitalizations for congestive heart failure (CHF) were observed. OPG and FGF23 were associated with all outcomes, with the highest hazard ratios (HRs) for OPG. In the final Cox regression model, adjusted for CV risk factors, including kidney function and all other investigated biomarkers, each standard deviation increase in OPG was associated with non-CV death (HR 1.76, 95% CI: 1.35–2.30), CV death (HR 2.18, 95% CI: 1.50–3.16), MACE (HR 1.38, 95% CI: 1.12–1.71) and hospitalization for CHF (HR 2.05, 95% CI: 1.56–2.69). Out of the nine biomarkers examined, stratification based on serum OPG best identified the CKD patients who were at the highest risk for any adverse CV outcome and mortality.


Supplementary Data
Table S1.Demographics and clinical parameters at baseline according to FGF23 quintiles (n=4246).
Table S3.Demographics and clinical parameters at baseline according to bone alkaline phosphatase (BAP) quintiles (n=4246).
Table S4.Demographics and clinical parameters at baseline according to C-Telopeptide of Type I Collagen (CTX1) quintiles (n=4246).
Table S5.Demographics and clinical parameters at baseline according to Procollagen I Intact N-terminal (P1NP) quintiles (n=4246).
Table S6.Demographics and clinical parameters at baseline according to phosphate quintiles (n=4246).
Table S7.Demographics and clinical parameters at baseline according to calcium quintiles (n=4246).
Table S8.Demographics and clinical parameters at baseline according to 25-OH Vitamin D quintiles (n=4246).
Table S11.Association of serum calcium levels with different outcomes.
Table S12.Association of 25-OH Vitamin D with different outcomes.
Table S13.Association of bone alkaline phosphatase (BAP) with different outcomes.
Table S14.Association of C-telopeptide of type I collagen (CTX1) with different outcomes.
Table S15.Association of serum phosphate levels with different outcomes.
Table S16.Association of procollagen I intact N-terminal (P1NP) with different outcomes.1 Table S1.Demographics and clinical parameters at baseline according to iFGF23 quintiles (n=4246).

Supplementary Figure S1. Risk of outcomes for each biomarker quintile in model 3.
Here presented data is the output of model 3 which adjusts for demographic characteristics and the other bone biomarkers.CV, cardiovascular; HR, hazard ratio; CI, confidence interval; MACE, major adverse cardiac event; CHF, hospitalization due to congestive heart failure; OPG, osteoprotegerin; iFGF23, intact fibroblast growth factor 23; iPTH, intact parathyroid hormone; BAP, bone alkaline phosphatase; CTX1, crosslinked C-telopeptide of type I collagen; P1NP, procollagen I intact N-terminal propetide.

Figure S1 .
Figure S1.Risk of outcomes for each biomarker quintiles in model 3.

Table S2 . Demographics and clinical parameters at baseline according to intact parathyroid hormone (iPTH) quintiles (n=4246).
Continuous variables are presented as mean and standard deviation or median and interquartile range.Categorical variables are presented as absolute numbers and as percentage of overall study population.iPTH, intact parathormone, eGFR, estimated glomerular filtration rate; UACR, urine albumin creatinine ratio; hsCRP, high-sensitivity C-reactive protein; LDL, low density lipoprotein; HDL, high density lipoprotein; BP, blood pressure; CVD, cardiovascular disease; BMI; body mass index, RASi; renin angiotensin system inhibitor.

Table S3 . Demographics and clinical parameters at baseline according to calcium quintiles (n=4246).
Continuous variables are presented as mean and standard deviation or median and interquartile range.Categorical variables are presented as absolute numbers and as percentage of overall study population.eGFR, estimated glomerular filtration rate; UACR, urine albumin creatinine ratio; hsCRP, high- sensitivity C-reactive protein; LDL, low density lipoprotein; HDL, high density lipoprotein; BP, blood pressure; CVD, cardiovascular disease; BMI; body mass index, RASi; renin angiotensin system inhibitor.

Table S6 . Demographics and clinical parameters at baseline according to C telopeptide of type 1 collagen (CTX1) quintiles (n=4246).
Continuous variables are presented as mean and standard deviation or median and interquartile range.Categorical variables are presented as absolute numbers and as percentage of overall study population.CTX1, C-Telopeptide of Type I Collagen; eGFR, estimated glomerular filtration rate; UACR, urine albumin creatinine ratio; hsCRP, high-sensitivity C-reactive protein; LDL, low density lipoprotein; HDL, high density lipoprotein; BP, blood pressure; CVD, cardiovascular disease; BMI; body mass index, RASi; renin angiotensin system inhibitor.

Table S7 : Demographics and clinical parameters at baseline according to phosphate quintiles (n=4246).
Continuous variables are presented as mean and standard deviation or median and interquartile range.Categorical variables are presented as absolute numbers and as percentage of overall study population.eGFR, estimated glomerular filtration rate; UACR, urine albumin creatinine ratio; hsCRP, high- sensitivity C-reactive protein; LDL, low density lipoprotein; HDL, high density lipoprotein; BP, blood pressure; CVD, cardiovascular disease; BMI; body mass index, RASi; renin angiotensin system inhibitor.

Table S8 : Demographics and clinical parameters at baseline according to procollagen 1 intact N terminal (P1NP) quintiles (n=4246).
Continuous variables are presented as mean and standard deviation or median and interquartile range.Categorical variables are presented as absolute numbers and as percentage of overall study population.P1NP, Procollagen I Intact N-Terminal; eGFR, estimated glomerular filtration rate; UACR, urine albumin creatinine ratio; hsCRP, high-sensitivity C-reactive protein; LDL, low density lipoprotein; HDL, high density lipoprotein; BP, blood pressure; CVD, cardiovascular disease; BMI; body mass index, RASi; renin angiotensin system inhibitor.

Table S15 . Association of serum phosphate levels with different outcomes.
Results are presented as hazard ratios with 95%-confidence intervals given in parentheses.Model 2: adjusted for age, sex, BMI, systolic blood pressure, LDL cholesterol, CRP, serum albumin, eGFR, UACR, diabetes mellitus, CVD, smoking, use of statins, use of RASi, use of thrombocyte aggregation inhibitors, use of betablockers, ongoing vitamin D therapy, and use of aldosterone antagonists.

Table S16 . Association of procollagen 1 intact N-terminal propeptide (P1NP) with different outcomes.
Results are presented as hazard ratios with 95%-confidence intervals given in parentheses.Model 2: adjusted for age, sex, BMI, systolic blood pressure, LDL cholesterol, CRP, serum albumin, eGFR, UACR, diabetes mellitus, CVD, smoking, use of statins, use of RASi, use of thrombocyte aggregation inhibitors, use of betablockers, ongoing vitamin D therapy, and use of aldosterone antagonists.Model 3: adjusted for parameters as in Model 2 plus OPG, BAP, calcium, phosphate, FGF23, CTX1, 25-OH vitamin D, and iPTH.